Subphenotypes in patients with acute respiratory distress syndrome treated with high-flow oxygen.

BACKGROUND: Acute respiratory distress syndrome (ARDS) subphenotypes differ in outcomes and treatment responses. Subphenotypes in high-flow nasal oxygen (HFNO)-treated ARDS patients have not been investigated. OBJECTIVES: To identify biological subphenotypes in HFNO-treated ARDS patients. METHODS: Secondary analysis of a prospective multicenter observational study including ARDS patients supported with HFNO. Plasma inflammation markers (interleukin [IL]-6, IL-8, and IL-33 and soluble suppression of tumorigenicity-2 [sST2]) and lung epithelial (receptor for advanced glycation end products [RAGE] and surfactant protein D [SP-D]) and endothelial (angiopoietin-2 [Ang-2]) injury were measured. These biomarkers and bicarbonate were used in K-means cluster analysis to identify subphenotypes. Logistic regression was performed on biomarker combinations to predict clustering. We chose the model with the best AUROC and the lowest number of variables. This model was used to describe the HAIS (High-flow ARDS Inflammatory Subphenotype) score. RESULTS: Among 41 HFNO patients, two subphenotypes were identified. Hyperinflammatory subphenotype (n = 17) showed higher biomarker levels than hypoinflammatory (n = 24). Despite similar baseline characteristics, the hyperinflammatory subphenotype had higher 60-day mortality (47 vs 8.3% p = 0.014) and longer ICU length of stay (22.0 days [18.0-30.0] vs 39.5 [25.5-60.0], p = 0.034). The HAIS score, based on IL-8 and sST2, accurately distinguished subphenotypes (AUROC 0.96 [95%CI: 0.90-1.00]). A HAIS score ≥ 7.45 was predictor of hyperinflammatory subphenotype. CONCLUSION: ARDS patients treated with HFNO exhibit two biological subphenotypes that have similar clinical characteristics, but hyperinflammatory patients have worse outcomes. The HAIS score may identify patients with hyperinflammatory subphenotype and might be used for enrichment strategies in future clinical trials.

Two New Neutrophil Subsets Define a Discriminating Sepsis Signature.

Rationale: Sepsis is the leading cause of death in adult ICUs. At present, sepsis diagnosis relies on nonspecific clinical features. It could transform clinical care to have immune-cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Objectives: To identify an early, specific immune signature of sepsis severity that does not overlap with other inflammatory biomarkers and that distinguishes patients with sepsis from those with noninfectious inflammatory syndrome. Methods: Mass cytometry combined with computational high-dimensional data analysis was used to measure 42 markers on whole-blood immune cells from patients with sepsis and control subjects and to automatically and comprehensively characterize circulating immune cells, which enables identification of novel, disease-specific cellular signatures. Measurements and Main Results: Unsupervised analysis of high-dimensional mass cytometry data characterized previously unappreciated heterogeneity within the CD64+ immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 (programmed death ligand 1) expression. These immature neutrophils exhibited diminished activation and phagocytosis functions. The proportion of CD123-expressing neutrophils correlated with clinical severity. Conclusions: This study showed that these two new neutrophil subsets were specific to sepsis and detectable through routine flow cytometry by using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.

Immunity and inflammation: the neglected key players in congenital heart disease?

Although more than 90% of children born with congenital heart disease (CHD) survive into adulthood, patients face significantly higher and premature morbidity and mortality. Heart failure as well as non-cardiac comorbidities represent a striking and life-limiting problem with need for new treatment options. Systemic chronic inflammation and immune activation have been identified as crucial drivers of disease causes and progression in various cardiovascular disorders and are promising therapeutic targets. Accumulating evidence indicates an inflammatory state and immune alterations in children and adults with CHD. In this review, we highlight the implications of chronic inflammation, immunity, and immune senescence in CHD. In this context, we summarize the impact of infant open-heart surgery with subsequent thymectomy on the immune system later in life and discuss the potential role of comorbidities and underlying genetic alterations. How an altered immunity and chronic inflammation in CHD influence patient outcomes facing SARS-CoV-2 infection is unclear, but requires special attention, as CHD could represent a population particularly at risk during the COVID-19 pandemic. Concluding remarks address possible clinical implications of immune changes in CHD and consider future immunomodulatory therapies.

Accuracy of cumulative volumes of fluid challenge to assess fluid responsiveness in critically ill patients with acute circulatory failure: a pharmacodynamic approach.

BACKGROUND: The relationship between the dose (volume of fluid) and the effect (increase of stroke volume [SV]) has been poorly described. We hypothesised that the analysis of the dynamic response of SV during fluid challenge (FC) helps to determine the optimal volume of FC, along with its diagnostic accuracy parameters for fluid responsiveness. METHODS: A prospective observational study was conducted in critically ill patients with circulatory failure. Patients monitored with oesophageal Doppler and assigned to an FC of 500 ml of crystalloid were included. The areas under the curve (AUC) and 95% confidence intervals (CI95) of the receiver operating characteristic curves for cumulative volumes from 50 to 450 ml were determined for fluid responsiveness (SV increase ≥15% from baseline) along with other parameters of diagnostic accuracy. In the pharmacodynamic analysis, dose-effect and dose-response models were constructed, with determination of median and 90% effective dose (ED50 and ED90). RESULTS: Forty-five patients were included. The AUC increased with cumulative volumes of FC up to 250 ml (AUC250 0.93 [CI95: 0.85-1.00]), followed by a plateau above 0.95 of AUC. The optimal volume was 250 ml, associated with a specificity of 0.89 [CI95: 0.78-1.00], a sensitivity of 0.92 [CI95: 0.69-1.00], and a threshold of 9.6% increase in SV. The ED50 was 156 [CI95: 136-177] ml and the ED90 was 312 [CI95: 269-352] ml. CONCLUSIONS: A volume of FC of 250 ml with a threshold of 9.6% increase in SV showed the highest accuracy in detecting fluid responsiveness in critically ill patients with shock. CLINICAL TRIAL REGISTRATION: .

Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study.

BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients. METHODS: The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later. RESULTS: Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality. CONCLUSIONS: Admission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Evaluation of glomerular filtration rate using iohexol plasma clearance in critically ill patients with augmented renal creatinine clearance: A single-centre retrospective study.

BACKGROUND: Augmented renal creatinine clearance (ARC) (≥130 ml min-1 1.73 m-2) is frequent in intensive care unit (ICU) patients and may impact patient outcome. OBJECTIVES: To compare glomerular filtration rate (GFR) measured with iohexol plasma clearance and creatinine clearance in critically ill patients with augmented renal clearance. DESIGN: Single-centre, retrospective study. SETTING: French University Hospital ICU from November 2016 to May 2019. PATIENTS: Adult patients with augmented renal clearance who had a measurement of iohexol plasma clearance. MAIN OUTCOME MEASURE: Agreement between 6 h creatinine clearance (6 h CrCl) and iohexol plasma clearance (GFRio). RESULTS: Twenty-nine patients were included. The median 6 h creatinine clearance was 195 [interquartile range (IQR) 162 to 251] ml min-1 1.73 m-2 and iohexol clearance was 133 [117 to 153] ml min-1 1.73 m-2. Sixteen patients (55%) had hyperfiltration (clearance >130 ml min-1 1.73 m-2) measured with iohexol clearance. Mean bias between iohexol and creatinine clearance was -80 [limits of agreement (LoA) -216 to 56 ml min-1 1.73 m-2]. For Cockcroft and Gault Modification of Diet in Renal Disease equation (MDRD), Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) formulae, mean biases were, respectively -27 (LoA -99 to 45), -14 (LoA -86 to 59) and 15 (LoA -33 to 64) ml min-1 1.73 m-2. CONCLUSION: In the present study, we found that in patients with augmented renal creatinine clearance, half of the patients do not have hyperfiltration using iohexol clearance measurements. We observed an important bias between 6 h CrCl and GFRio with large LoA. In critically patients with ARC, 6 h CrCl does not reliably estimate GFR and 6 h CrCl nearly systematically overestimates renal function. Comparison of creatinine-based GFR estimations and GFRio show acceptable bias but wide LoA.

Monitoring haemodynamic response to fluid-challenge in ICU: comparison of pressure recording analytical method and oesophageal Doppler: A prospective observational study.

BACKGROUND: The ability of the pressure recording analytical method (PRAM) in tracking change in cardiac output (ΔCO) after a fluid challenge in ICU needs to be evaluated with the most contemporary comparison methods recommended by experts. OBJECTIVE: Our objective was to report the trending ability of PRAM in tracking ΔCO after a fluid challenge in ICU and to compare this with oesophageal Doppler monitoring (ODM). DESIGN: Prospective, observational study. SETTING: Hôpital Lariboisière and Hôpital Européen George Pompidou, Paris, France, from April 2016 to December 2017. PATIENTS: Critically ill patients admitted to ICU with monitoring of CO monitored by ODM and invasive arterial pressure. INTERVENTION: ΔCO after fluid challenge was simultaneously registered with ODM and PRAM connected to the arterial line. MAIN OUTCOME MEASURE: Polar statistics (mean angular bias, radial limits of agreement and polar concordance rate) and clinical concordance evaluation (error grid and clinical concordance rate). Predictors of bias were determined. RESULTS: Sixty-eight fluid challenge were administered in 49 patients. At the time of fluid challenge, almost all were mechanically ventilated (99%), with 85% receiving norepinephrine. Admission diagnosis was septic shock in 70% of patients. Patients had a Sequential Organ Failure Assessment score of 10 [7 to 12] and a median Simplified Acute Physiology Score II of 61 [49 to 69]. Relative ΔCO bias was 7.8° (6.3°) with radial limits of agreement of ±41.7°, polar concordance rate 80% and clinical concordance rate 74%. ΔCO bias was associated with baseline bias (P = 0.007). Baseline bias was associated with radial location of the arterial line (P = 0.03). CONCLUSION: When compared with ODM, PRAM has insufficient performance to track ΔCO induced by fluid challenge in ICU patients. Baseline bias is an independent predictor of trending bias. TRIAL REGISTRATION: IRB 00010254-2016-033.

Protracted immune disorders at one year after ICU discharge in patients with septic shock.

BACKGROUND: Sepsis is a leading cause of mortality and critical illness worldwide and is associated with an increased mortality rate in the months following hospital discharge. The occurrence of persistent or new organ dysfunction(s) after septic shock raises questions about the mechanisms involved in the post-sepsis status. The present study aimed to explore the immune profiles of patients one year after being discharged from the intensive care unit (ICU) following treatment for abdominal septic shock. METHODS: We conducted a prospective, single-center, observational study in the surgical ICU of a university hospital. Eighty-six consecutive patients admitted for septic shock of abdominal origin were included in this study. Fifteen different plasma biomarkers were measured at ICU admission, at ICU discharge and at one year after ICU discharge. Three different clusters of biomarkers were distinguished according to their functions, namely: (1) inflammatory response, (2) cell damage and apoptosis, (3) immunosuppression and resolution of inflammation. The primary objective was to characterize variations in the immune status of septic shock patients admitted to ICU up to one year after ICU discharge. The secondary objective was to evaluate the relationship between these biomarker variations and patient outcomes. RESULTS: At the onset of septic shock, we observed a cohesive pro-inflammatory profile and low levels of inflammation resolution markers. At ICU discharge, the immune status demonstrated decreased but persistent inflammation and increased immunosuppression, with elevated programmed cell death protein-1 (PD-1) levels, and a counterbalanced resolution process, with elevated levels of interleukin-10 (IL-10), resolvin D5 (RvD5), and IL-7. One year after hospital discharge, homeostasis was not completely restored with several markers of inflammation remaining elevated. Remarkably, IL-7 was persistently elevated, with levels comparable to those observed after ICU discharge, and PD-1, while lower, remained in the elevated abnormal range. CONCLUSIONS: In this study, protracted immune disturbances were observed one year after ICU discharge. The study results suggested the presence of long-lasting immune illness disorders following a long-term septic insult, indicating the need for long-term patient follow up after ICU discharge and questioning the use of immune intervention to restore immune homeostasis after abdominal septic shock.

Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism.

Monocytes have a crucial role in both proinflammatory and anti-inflammatory phenomena occurring during sepsis. Monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2 and their cognate ligands. However, little is known about the roles of these cells and chemokines during the acute phase of inflammation in sepsis. Using intravital microscopy in a murine model of polymicrobial sepsis, we showed that inflammatory Ly6C(high) monocytes infiltrated kidneys, exhibited altered motility, and adhered strongly to the renal vascular wall in a chemokine receptor CX3CR1-dependent manner. Adoptive transfer of Cx3cr1-proficient monocyte-enriched bone marrow cells into septic Cx3cr1-depleted mice prevented kidney damage and promoted mouse survival. Modulation of CX3CR1 activation in septic mice controlled monocyte adhesion, regulated proinflammatory and anti-inflammatory cytokine expression, and was associated with the extent of kidney lesions such that the number of lesions decreased when CX3CR1 activity increased. Consistent with these results, the pro-adhesive I249 CX3CR1 allele in humans was associated with a lower incidence of AKI in patients with sepsis. These data show that inflammatory monocytes have a protective effect during sepsis via a CX3CR1-dependent adhesion mechanism. This receptor might be a new therapeutic target for kidney injury during sepsis.

Innate response activator B cells: origins and functions.

Innate response activator (IRA) B cells are a subset of B-1a derived B cells that produce the growth factors granulocyte macrophage colony stimulating factor and IL-3. In mouse models of sepsis and pneumonia, B-1a B cells residing in serosal sites recognize bacteria, migrate to the spleen or lung, and differentiate to IRA B cells that then contribute to the host response by amplifying inflammation and producing polyreactive IgM. In atherosclerosis, IRA B cells accumulate in the spleen, where they promote extramedullary hematopoiesis and activate classical dendritic cells. In this review, we focus on the ontogeny and function of IRA B cells in acute and chronic inflammation.

Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium.

RATIONALE: Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)(high) and reparative Ly-6C(low) monocytes/macrophages (Mo/MΦ). According to 1 model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6C(low) monocyte production but dispensable to Ly-6C(low) macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity. OBJECTIVE: This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MΦ accumulation scenarios. METHODS AND RESULTS: We show that Ly-6C(high) monocytes infiltrate the infarcted myocardium and, unlike Ly-6C(low) monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C(high) monocytes accrue in response to a brief C-C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C(high) monocytes give rise to reparative Ly-6C(low) F4/80(high) macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C(high) monocytes express heightened levels of C-C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function. CONCLUSIONS: Ly-6C(high) monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.

Spontaneous soft-tissue hemorrhage in anticoagulated patients: safety and efficacy of embolization.

OBJECTIVE: The purpose of this study was to report the effectiveness and safety of selective arterial embolization for the management of anticoagulation-related soft-tissue bleeding. MATERIALS AND METHODS: All consecutive patients from June 1, 2003, to June 1, 2010, with intractable anticoagulation-related soft-tissue bleeding treated by embolization were included. The clinical files, MDCT angiographic examinations, and procedure details were reviewed. The primary goal of this study was to report the safety and efficacy of embolization for the management of anticoagulation-related soft-tissue bleeding. The secondary goal was to evaluate the correlation between the MDCT angiography (MDCTA) findings and conventional catheter angiography. RESULTS: Thirty-six consecutive patients were included. All patients were under anticoagulant therapy. Overdosage of the anticoagulant was found in 12 (33%) patients. MDCT was performed with multiphasic contrast media injection in 30 patients (83%) and showed extravasation in 22 (73.3%) of those 30 patients. Catheter angiography revealed extravasation in 27 of 36 (75%) patients, and no active bleeding was observed in nine patients who were empirically embolized. The sensitivity of MDCTA for depicting ongoing active bleeding was 87%. The transfusion requirement for RBC units decreased from 4.0 (range, 0-12.0) before to 0 (range, 0-4.0) after embolization. Nine patients underwent a second embolization but only one in the same vascular territory. Eleven patients died within 30 days despite the embolization. No complications related to embolization were reported. CONCLUSION: Anticoagulation-related soft-tissue bleeding can be efficiently and safely treated by selective arterial embolization. However, this serious pathologic condition may be fatal in many cases, and rebleeding is not rare. MDCTA could help to guide treatment.

Compartmentalization of the inflammatory response during bacterial sepsis and severe COVID-19.

Acute infections cause local and systemic disorders which can lead in the most severe forms to multi-organ failure and eventually to death. The host response to infection encompasses a large spectrum of reactions with a concomitant activation of the so-called inflammatory response aimed at fighting the infectious agent and removing damaged tissues or cells, and the anti-inflammatory response aimed at controlling inflammation and initiating the healing process. Fine-tuning at the local and systemic levels is key to preventing local and remote injury due to immune system activation. Thus, during bacterial sepsis and Coronavirus disease 2019 (COVID-19), concomitant systemic and compartmentalized pro-inflammatory and compensatory anti-inflammatory responses are occurring. Immune cells (e.g., macrophages, neutrophils, natural killer cells, and T-lymphocytes), as well as endothelial cells, differ from one compartment to another and contribute to specific organ responses to sterile and microbial insult. Furthermore, tissue-specific microbiota influences the local and systemic response. A better understanding of the tissue-specific immune status, the organ immunity crosstalk, and the role of specific mediators during sepsis and COVID-19 can foster the development of more accurate biomarkers for better diagnosis and prognosis and help to define appropriate host-targeted treatments and vaccines in the context of precision medicine.

Systemic tolerance of intravenous milrinone administration for cerebral vasospasm secondary to non-traumatic subarachnoid hemorrhage.

PURPOSE: Delayed cerebral ischemia (DCI) is a severe subarachnoid hemorrhage (SAH) complication, closely related to cerebral vasospasm (CVS). CVS treatment frequently comprises intravenous milrinone, an inotropic and vasodilatory drug. Our objective is to describe milrinone's hemodynamic, respiratory and renal effects when administrated as treatment for CVS. METHODS: Retrospective single-center observational study of patients receiving intravenous milrinone for CVS with systemic hemodynamics, oxygenation, renal disorders monitoring. We described these parameters' evolution before and after milrinone initiation (day - 1, baseline, day 1 and day 2), studied treatment cessation causes and assessed neurological outcome at 3-6 months. RESULTS: Ninety-one patients were included. Milrinone initiation led to cardiac output increase (4.5 L/min [3.4-5.2] at baseline vs 6.6 L/min [5.2-7.7] at day 2, p < 0.001), Mean Arterial Pressure decrease (101 mmHg [94-110] at baseline vs 95 mmHg [85-102] at day 2, p = 0.001) norepinephrine treatment requirement increase (32% of patients before milrinone start vs 58% at day 1, p = 0.002) and slight PaO2/FiO2 ratio deterioration (401 [333-406] at baseline vs 348 [307-357] at day 2, p = 0.016). Milrinone was interrupted in 8% of patients. 55% had a favorable outcome. CONCLUSION: Intravenous milrinone for CVS treatment seems associated with significant impact on systemic hemodynamics leading sometimes to treatment discontinuation.

Relationship between positive end-expiratory pressure levels, central venous pressure, systemic inflammation and acute renal failure in critically ill ventilated COVID-19 patients: a monocenter retrospective study in France.

BACKGROUND: The role of positive pressure ventilation, central venous pressure (CVP) and inflammation on the occurrence of acute kidney injury (AKI) have been poorly described in mechanically ventilated patient secondary to coronavirus disease 2019 (COVID-19). METHODS: This was a monocenter retrospective cohort study of consecutive ventilated COVID-19 patients admitted in a French surgical intensive care unit between March 2020 and July 2020. Worsening renal function (WRF) was defined as development of a new AKI or a persistent AKI during the 5 days after mechanical ventilation initiation. We studied the association between WRF and ventilatory parameters including positive end-expiratory pressure (PEEP), CVP, and leukocytes count. RESULTS: Fifty-seven patients were included, 12 (21%) presented WRF. Daily PEEP, 5 days mean PEEP and daily CVP values were not associated with occurrence of WRF. 5 days mean CVP was higher in the WRF group compared to patients without WRF (median [IQR], 12 mm Hg [11-13] vs. 10 mm Hg [9-12]; P=0.03). Multivariate models with adjustment on leukocytes and Simplified Acute Physiology Score (SAPS) II confirmed the association between CVP value and risk of WRF (odd ratio, 1.97; 95% confidence interval, 1.12-4.33). Leukocytes count was also associated with occurrence of WRF in the WRF group (14 G/L [11-18]) and the no-WRF group (9 G/L [8-11]) (P=0.002). CONCLUSIONS: In mechanically ventilated COVID-19 patients, PEEP levels did not appear to influence occurrence of WRF. High CVP levels and leukocytes count are associated with risk of WRF.